Levings Application 1 Flashcards
1
Q
MHC protein numbers (2)
A
- humans have 6 different genes encoding MHC proteins, with 2 copies of each gene
- total of 12 copies
2
Q
MHC class I (2)
A
- 3 MHC class I proteins
- HLA-A, HLA-B, and HLA-C
3
Q
HLA
A
- human leukocyte antigen
4
Q
MHC class II (2)
A
- 3 MHC class II proteins
- HLA-DP, HLA-DQ, HLA-DR
5
Q
how are MHC proteins key for diversity (3)
A
- many different alleles for each MHC gene
- polymorphism maximizes probability of binding to peptides from pathogens
- particular combination of 12 HLAs we each express defines our tissue type
6
Q
MHC diversity and transplantation
A
- MHC diversity is why transplanted cells/organs are recognized as non-self
7
Q
what is the mouse version of the human HLA complex
A
- mouse H-2 complex
8
Q
allorecognition
A
- the ability of an individual organism to distinguish its own tissues from those of another
9
Q
allorecognition pathways (3)
A
- direct pathway
- indirect pathway
- semidirect pathway
10
Q
what percentage of recipient T cells participate in direct pathway allorecognition
A
- 1-7% of T cells participate in direct recognition for any given donor/host pair depending on degree of donor mismatch
11
Q
allorecognition: direct pathway
A
- donor APC presents MHC-donor antigen complex to the TCR of a recipient T cell
12
Q
allorecognition: direct presentation steps (2)
A
- donor-derived DCs leave the graft, migrate to LNs, and stimulate naive alloantigen-specific T cells
- activated T cells traffic to graft where they can be restimulated by donor cells expressing MHC and initiate an immune response
13
Q
which form of presentation is important in early allograft responses
A
- direct pathway
14
Q
allorecognition: indirection pathway
A
- transplanted antigens are processed and presented on recipient MHC from recipient APC to a recipient T cell
15
Q
allorecognition: semidirect pathway
A
- transplanted MHC-donor antigen are presented by a recipient APC to a recipient T cells
16
Q
direct allorecognition types (2)
A
- peptide centric: donor peptide of donor peptide-MHC is recognized
- MHC centric: MHC peptide of donor peptide-MHC is recognized
17
Q
transplants vs normal immune response
A
- capacity of donor-derived cells to participate
- direct recognition of alloantigens
- high freq. of alloAg specific cells in both naive and memory T cell pool
- lifelong presence of Ag
18
Q
infection in transplantation: 1-12 months after transplant (2)
A
- maximum immune suppression due to immunosuppressants
- opportunistic infections, relapses, and reactivations
19
Q
infection in transplantation: over 12 months (2)
A
- late-onset infections
- opportunistic infections and community-acquired infections
20
Q
clinical application of strategies to induce tolerance (2)
A
- central tolerance strategies (deletion)
- peripheral tolerance strategies (anergy & suppression)
21
Q
clinical application of strategies to induce tolerance: central tolerance
A
- HSC transplantation to re-set central tolerance
22
Q
clinical application of strategies to induce tolerance: peripheral tolerance (2)
A
- co-stimulation blockade/modulation
- cell therapy with regulatory immune cells
- in vivo boosting of regulatory immune cells
23
Q
HSC transplantation: autologous transplantation
- benefit
- risks (2)
A
- benefit: no risk of graft versus host disease
- risk: incomplete ablation of autoreactive cells
- risk: same genetic risk factors in immune cells
24
Q
HSC transplantation: allogeneic transplantation
- benefits (2)
- risk
A
- benefit: reduced genetic risk of autoimmunity
- benefit: assuming complete reconstitution, no space for autoreactive cells
- risk: graft versus host disease
25
allogeneic
- individuals of the same species who are genetically different and immunologically incompatible
26
autologous
- cell/tissues obtained from same individual
27
graft versus host disease
- T cells of the donated stem cells/bone marrow cells attack the host cells
28
Tregs as cellular therapy to induce transplantation tolerance: Treg sources (2)
- can be taken from patient
- can be from third source (blood donation, cord blood, thymus, etc)
29
Tregs as cellular therapy to induce transplantation tolerance (3)
- Tregs taken from sources and undergo in vitro expansion
- cell therapy to insert Tregs back into patient
- Tregs police immune system, regulate and control immune responses to stop graft rejection and graft vs host disease
30
Treg cell therapies examples (7)
- type 1 & 2 diabetes
- MS
- rhematoid arthritis
- IBD
- allergies
- allograft rejection
- graft versus host disease
31
strategies to block Tregs applications (3)
- cancer
- chronic infections
- vaccination
32
regulatory cell therapy paper: kidney rejection outcomes
- CTG had slightly lower rate of biopsy confirmed acute rejection compared to RGT
33
regulatory cell therapy paper: infection outcomes
- CTG had lower rate of infection compared to RGT
34
regulatory cell therapy paper: effects on immune cell populations
- RGT patients had major alterations in absolute and relative blood immune cell population composition compared with healthy controls
35
regulatory cell therapy paper: effects on Tregs
- no significant difference in number/proportions of Tregs between groups 60 weeks post-kidney transplant
36
resetting central tolerance: HSCT for solid organ transplant steps (7)
1. conditioning drug regime
2. transplantation of donor BM
3. donor HSC engraftment
4. multilineage chimerism
5. peripheral tolerance (intragraft)
6. peripheral tolerance (secondary lymphoid organs)
7. central tolerance
37
re-setting central tolerance: HSCT for solid organ transplant; thymus (4)
- recipient and donor bone marrow enter thymus
- alloreactive T cell from both donor and recipient in thymus
- alloreactive recipient and donor T cells negatively selected and die
- mature, non-alloreactive T cells escape to blood as a mixed chimera
